public assessment report decentralised procedure … · par saline nebuliser solution (sodium...

PAR Saline Nebuliser Solution (Sodium Chloride 0.9% w/v) UK/H/2088/001/DC

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Public Assessment Report

Decentralised Procedure

SALINE NEBULISER SOLUTION (SODIUM CHLORIDE 0.9% W/V)

UK/H/2088/001/DC UK licence no: PL 18023/0006

BREATH LIMITED


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LAY SUMMARY

On 23rd October 2009, the MHRA granted Breath Limited a Marketing Authorisation (licence) for the medicinal product Saline Nebuliser Solution (Sodium Chloride 0.9% w/v). This prescription-only product (POM) is used to dilute medicines that are used in a nebuliser. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Saline Nebuliser Solution (Sodium Chloride 0.9% w/v) outweigh the risks; hence a Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Module 2: Summary of Product Characteristics Page 4 Module 3: Product Information Leaflets Page 22 Module 4: Labelling Page 24 Module 5: Scientific Discussion Page 28 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6 Steps taken after initial procedure


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Module 1

Product Name

Saline Nebuliser Solution (Sodium Chloride 0.9% w/v)

Type of Application

Article 10a, Well-established use

Active Substance

Sodium chloride

Form

Nebuliser solution

Strength

0.9% sodium chloride

MA Holder

Breath Limited, Unit 2, Eastman Way, Stevenage, Hertfordshire, SG1 4SZ

Reference Member State

United Kingdom

Concerned Member States

Malta

Procedure Number

UK/H/2088/001/DC

Timetable

Day 150 – 15th August 2009


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Saline Nebuliser Solution (Sodium Chloride 0.9% w/v)

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 9 mg of Sodium Chloride

For a full list of excipients see section 6.1 3 PHARMACEUTICAL FORM

Solution for nebulisation

Clear, colourless solution in a clear, plastic single dose ampoule 4 CLINICAL PARTICULARS 4.1 Therapeutic indications

For dilution of solutions for nebulisation. 4.2 Posology and method of administration

Adults, children and elderly: use as directed by the physician. Saline Nebuliser Solution is only to be used as a diluent for diluting products for nebulisation and should not be used on its own. It should not be taken orally or administered parenterally. Each ampoule contains 2.5 ml of solution. Refer to the patient information leaflet of the nebulised product to be diluted that your physician has prescribed you for detailed instructions on use of this solution as a diluent. To ensure accurate dosing it is recommended that a dosing syringe is used if necessary. Method of Administration: By inhalation from a suitable nebuliser or an intermittent positive pressure ventilator after the single dose ampoule has been opened and its contents transferred to the nebuliser chamber. Administration should be in accordance with the manufacturer’s instructions for the device. 1. Prepare the nebuliser by following the manufacturer's instructions and the advice of your doctor. 2. The nebulised product to be diluted should be introduced into the nebuliser chamber as instructed in

the appropriate patient information leaflet. 3. Carefully separate a new saline ampoule from the strip. Never use an ampoule that has been opened

already. 3. Open the ampoule by simply twisting off the top, always taking care to hold it in an upright

position. 4. Squeeze the contents of the plastic ampoule or use a dosing syringe as required into the nebuliser

chamber and swirl gently to mix. 5. Assemble the nebuliser and use it as directed by your doctor. 6. After nebulisation, clean the nebuliser according to the manufacturer’s instructions. It is important

that the nebuliser is kept clean. As the single dose units contain no preservatives it is important that the contents are used immediately after opening and a fresh ampoule is used for each administration to avoid microbial contamination. Partly used, opened or damaged single dose units should be discarded. Any solution remaining in the nebuliser chamber should be discarded.

4.3 Contraindications The solution should not be administered orally or parenterally.


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4.4 Special warnings and precautions for use Do not use unless the product is clear and the pack intact. Discard any surplus after use. Saline Nebuliser Solution should be used with a nebuliser, only under the direction of a physician. Patients using nebuliser solutions at home should be warned that if the usual relief is diminished or the usual duration of action reduced, they should consult their doctor.

4.5 Interaction with other medicinal products and other forms of interaction

Not known. 4.6 Pregnancy and lactation

As with most medicines, consult your doctor first if you are pregnant or breastfeeding. 4.7 Effects on ability to drive and use machines

Not known. 4.8 Undesirable effects

Saline Nebuliser Solution is not expected to cause any undesirable effects in normal use. 4.9 Overdose

Substantial oral ingestion may require the use of a diuretic to remove excess sodium. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Isotonic (0.9% w/v) sodium chloride solution is widely used for dilution purposes. 5.2 Pharmacokinetic properties

Not applicable 5.3 Preclinical safety data

There are no findings of relevance to the prescriber other than those already mentioned elsewhere in the SPC. Please refer to the product to be reconstituted.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Water for Injections 6.2 Incompatibilities

Not applicable 6.3 Shelf life

24 months

Ampoules removed from the foil overwrap should be used within 90 days.

Use immediately after first opening of the ampoule. Discard any unused contents. 6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature and contents of container

A unit dose blow moulded hermetically sealed low density polyethylene ampoule containing 2.5 ml of solution. Strips of ten ampoules are overwrapped in an aluminium laminate foil pack. Saline Nebuliser Solution is available in boxes containing 20, 60 or 100 ampoules.

6.6 Special precautions for disposal

No special requirements.


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7 MARKETING AUTHORISATION HOLDER Breath Limited Unit 2, Eastman Way, Stevenage, Hertfordshire, SG1 4SZ UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 18023/0006 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 23/10/2009 10 DATE OF REVISION OF THE TEXT

23/10/2009


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Module 3


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Module 4 Labelling


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Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK and Malta agreed to grant a marketing authorisation for the medicinal product Saline Nebuliser Solution (Sodium Chloride 0.9% w/v) on 15th August 2009. This product was assessed by the Decentralised Procedure (UK/H/2088/001/DC), with the UK as Reference Member State. A subsequent national licence was granted in the UK on 23rd October 2009. The product is a prescription-only product for dilution of solutions for nebulisation. This is an application made under Article 10a of 2001/83 EC, as amended, a well-established use application for a diluent of solutions for nebulisation. The product contains the active ingredient sodium chloride. No new preclinical studies were conducted, which is acceptable given that the application is submitted under Article 10a, a well-established use application. No clinical studies were conducted, which is acceptable given that the application is submitted under Article 10a, a well-established use application. The RMS has been assured that acceptable standards of GMP are in place for this product type at all sites responsible for the manufacture and assembly of this product. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. The decentralised procedure was completed at Day 150 (15th August 2009), with the reference member state and all concerned member states agreeing that the licence was approvable. The national phase of the decentralised procedure was completed in the UK on 23rd October 2009.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State Saline Nebuliser Solution

(Sodium Chloride 0.9% w/v) Name(s) of the active substance(s) (INN) Sodium chloride Pharmacotherapeutic classification (ATC code) Solvents and diluting agents (V07 AB) Pharmaceutical form and strength(s) 0.9% w/v Reference numbers for the Decentralised Procedure UK/H/2088/001/DC Reference Member State United Kingdom Member States concerned Malta Marketing Authorisation Number(s) PL 18023/0006 Name and address of the authorisation holder Breath Limited

Unit 2, Eastman Way, Stevenage, Hertfordshire, SG1 4SZ UK


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN: Sodium chloride Other names: Common salt, table salt, halite CAS Registry No: 7647-14-5 Molecular Formula: NaCl Molecular Weight: 58.443 Appearance: White or colourless crystals, freely soluble in water, practically

insoluble in ethanol Sodium chloride is the subject of a European Pharmacopoeia monograph. Synthesis of the drug substance from the designated starting materials has been adequately described, and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant certificates of analysis. All potential known impurities have been identified and characterised. Appropriate proof of structure data has been supplied for the active pharmaceutical ingredient. An appropriate specification is provided for the active substance sodium chloride that is in compliance with the European Pharmacopoeia monograph. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided and comply with the proposed specification. Satisfactory specifications have been provided for all packaging used to store the active substance. A declaration has been provided that the primary packaging complies with current regulations concerning contact with foodstuff. A suitable retest period has been assigned, based on stability data from studies performed in-line with current guidelines. P Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipient water for injections. This excipient complies with its European Pharmacopoeia monograph. No materials of animal or human origin are used in the production of water for injections. Pharmaceutical Development The applicant has provided a suitable product development rationale and data.

Manufacture Satisfactory batch formulae have been provided for the manufacture of the product along with an appropriate account of the manufacturing process. Suitable in-process controls are applied during the manufacturing process to ensure the quality of the product. The manufacturing process has been validated and has shown satisfactory results.


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Control of Drug Product The finished product specification proposed is acceptable and provides an assurance of the quality of the finished product. The analytical methods used have been suitably validated. Batch analysis data have demonstrated compliance with the proposed specification. Satisfactory data on the characterisation of impurities have been provided. Reference Standards or Materials Certificates of analysis for all reference standards used have been provided and are satisfactory. Container Closure System The finished product is packaged into blow-moulded hermetically sealed low-density polyethylene ampoules containing 2.5ml of solution. Strips of 10 ampoules are overwrapped in aluminium laminate foil packs and packaged in pack sizes of 20, 60 or 100 ampoules. Stability of the Drug Product Stability data have been provided to support a shelf-life of 24 months, with the storage instructions “Do not store above 25°C” and “Do not refrigerate of freeze”. Ampoules removed from the foil overwrap should be used within 90 days and contents of ampoules should be used immediately after opening. Any unused contents should be discarded. Bioequivalence/Bioavailability Certificates of analysis have been provided for batches of test and reference product used in the bioequivalence studies. SPC, PIL, Labels The SPC, PIL and labels are pharmaceutically acceptable. The PIL is in compliance with current guidelines and user testing results have been submitted. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. CONCLUSION It is recommended that a marketing authorisation is granted for this application. III.2 PRE-CLINICAL ASPECTS Sodium chloride is widely used as a diluent for medical solutions, including those to be delivered via a nebuliser. The proposed product is not indicated on the basis of a claim of efficacy but purely as a diluent for nebuliser solutions. The safety of sodium chloride is well-established having been in clinical use for many years. As such, the applicant has not provided additional studies and further studies are not required. An overview based on literature review is, thus, appropriate. The preclinical expert report has been written by an appropriately qualified person and is a suitable summary of the preclinical aspects of the dossier.


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III.3 CLINICAL ASPECTS CLINICAL PHARMACOLOGY/EFFICACY Saline solution has been used for over 30 years as a diluent for nebulised active products. It is a well-established fact that inhaled hypertonic saline is beneficial in restoring airways surface liquid in cystic fibrosis patients, and thereby increasing mucociliary clearance and improving lung function. No new studies have been submitted and none are required for an application of this type. SAFETY There are no new or unexpected clinical safety concerns with the use of this product. The good safety profile accounts for the widespread use as a diluent. The summary of product characteristics incorporates no safety warnings or potential side effects from the use of this product as a diluent, and this is appropriate. Likewise, there are no cautions with use in pregnancy, driving, etc. In the UK dietary reference values have been published for sodium. The reference nutrient intake for adults is 1.6g of sodium (70 mmol) daily. The minimal quantities that would enter the circulation from inhaled diluent of 0.9% sodium chloride would not impact this daily intake. The obvious and well-known side effect of an excess of salt intake would be development of high blood pressure, but the content of the diluent would have to be excessive to cause such a concern. Indeed, 0.9% saline has been used twice daily as a control in a 48-week study investigating the long-term effects of inhaled hypertonic saline in patients with cystic fibrosis with no adverse events of concern reported as purely due to normal saline. EXPERT REPORT A satisfactory clinical expert report has been submitted, which has been written by an appropriately qualified physician. SUMMARY OF PRODUCT CHARACTERISTICS (SPC) This is satisfactory and consistent with the SPC of similar products.

PATIENT INFORMATION LEAFLET (PIL) This is satisfactory and consistent with the SPC. LABELLING These are satisfactory. CONCLUSION The efficacy of this product is not of question as Saline Nebuliser Solution (Sodium Chloride 0.9% w/v) is used as a diluent for other medicinal products used for nebulisation. The safety of saline as a nebuliser diluent has been well-established for many years now, and there is no new information that would suggest that the profile has changed. Saline solution is used in a widespread manner as the diluent of choice for nebulisers The benefit-risk balance is therefore favourable and this product is approvable. The SPC, PIL and packaging are satisfactory and consistent with those for the reference product.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Saline Nebuliser Solution (Sodium Chloride 0.9% w/v) are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY No new clinical data were submitted and none are required for an application of this type. No new or unexpected safety concerns arise from this application. The SPC, PIL and labelling are satisfactory and consistent with those for other similar products. RISK-BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The safety of saline as a nebuliser diluent has been well-established for many years now, and there is no new information that would suggest that the profile has changed. The risk-benefit is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

public assessment report decentralised procedure … · par saline nebuliser solution (sodium...

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